KR820001307B1 - Process for preparation of amdidino-benzylpyrimidines - Google Patents

Abstract

Title compd. I (R1,R2,R3 = H, Me, MeO, Cl; R4 = C1-6 alkyl, benzyl; R5,R6 = H, C1-4 alkyl, benzyl, Ph, cyclohexyl, furfuryl), useful as antibiotics, were prepd. by reacting compd. II with amine(III). Thus, 16.2 g N-[4-amino-5-(3,4,5-trimethoxybenzyl)-pyrimidin-2-yl -acetamido ethyl ester was dissolved in 120 ml pyridine, inwhich 14 ml satd. ammonium soln. (dissolved in EtOH) was added and stirred at 10≰C for 12 hr, vacuum concentrated, and recrystallized to give 8.6g N-[4-amino-5-(3,4,5-trimethoxybenzyl) -pyrimidin -2-yl acetamidine(m.p. 207≰C).

Description

Method for preparing amidino-benzylpyrimidine

The present invention relates to a process for preparing novel amidino-benzylpyrimides represented by the following general formula (I) and addition salts with pharmacologically usable acids.

, 또는 5-6개의 요소를 가지며 서로 동일하거나 상이한 1-3개의 이종원자, 즉 질소 또는 산소를 함유하고 또한 염소, 메틸 또는 메톡시기로 치환될 수 있는 이종환형 고리이다.)이거나, 또는 R⁵및 R⁶는 모두 그에 결합된 질소원자화 함께 5-7개의 요소를 가지며 산소나 ＞N-Y 그룹(Y는 메틸, 벤질, 또는 페닐이다)을 함유하는 포화된 이종환형 고리를 나타낸다. 약리적으로 허용되는 염을 제조하는 데에 사용되는 통상적인 산으로 염산, 질산, 황산, 인산, 초산, 젖산, 시트릴산 및 살리실산을 들 수가 있다. 대개 치환제 R¹,R²및 R₃는 벤젠고리의 3-,4- 및 5- 위치에 존재한다.Wherein R ¹ , R ² and R ³ are the same or different and are hydrogen, methyl, methoxy, or chlorine, R ⁴ is alkyl having 1-6 carbon atoms, or benzyl, and R ⁵ and R ⁶ are the same as each other or Hydrogen, lower alkyl having 1-4 carbon atoms, substituted or unsubstituted benzyl, phenyl, cyclohexyl, adamantyl or furfuryl, or one of R ⁵ and R ⁶ is -C ₆ H ₄ -SO _2- NH-R ⁷ groups (R ⁷

Or heterocyclic ring having 5-6 elements and containing 1-3 heteroatoms identical or different from one another, ie nitrogen or oxygen, and which may also be substituted with chlorine, methyl or methoxy groups), or R ⁵ And R ⁶ both represent a saturated heterocyclic ring having 5-7 elements with the nitrogen atomization attached thereto and containing oxygen or> NY group (Y is methyl, benzyl, or phenyl). Typical acids used to prepare pharmacologically acceptable salts include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid and salicylic acid. Usually substituents R ¹ , R ² and R ₃ are present in the 3-, 4- and 5-positions of the benzene ring.

또는 피리미디-2-닐, 4-메틸-피리미디-2-닐, 5-메틸-피리미디-2-닐, 5-이소푸로필, 피리미디-2-닐, 5-메톡시-피리미디-2-닐, 6-메톡시-피리다조닐-3-릴, 3-메톡시-피라지-2-닐, 5-메틸-이소옥사졸-3-릴 또는 2-피리디닐임)이며, R¹, R²및 R³는 앞에서와 동일한 의미를 갖는 것들이다.Among the compounds of general formula (I), common are lower alkyl or benzene in which R ⁴ is 1-4 carbon atoms, and the same or different R ⁵ and R ⁶ are hydrogen, lower alkyl having 1-4 carbon atoms, benzyl, Benzyl, or both R ⁵ and R ⁶ represent polymethylenes of 4- or 5 methylene groups which may be interrupted by oxygen or> NY (Y is methyl, benzyl or phenyl), or R ⁵ is hydrogen and R ⁶ Is -C ₆ H ₄ -SO ₂ NH-R ⁷ (R ⁷ is

Or pyrimidin-2-yl, 4-methyl-pyrimidin-2-yl, 5-methyl-pyrimidin-2-yl, 5-isofurophyll, pyrimidin-2-yl, 5-methoxy-pyrimidi -2-yl, 6-methoxy-pyridazonyl-3-yl, 3-methoxy-pyrazin-2-yl, 5-methyl-isoxazol-3-yl or 2-pyridinyl), R ¹ , R ² and R ³ have the same meanings as above.

Among the compounds of the general formula (I), more general compounds are those in which R ¹ , R ² and R ³ are hydrogen, methyl or methoxy groups, and in particular, R ¹ , R ² and R ³ are 3-, 4 of benzyl groups. And are in the 5-position and each is a methoxy group.

Compounds of formula (I) have antibiotics against diseases caused by bacteria and protozoa, and when used in combination with sulfonamides, bactericidal activity is enhanced. This compound can be used, for example, in the treatment of bacterial infectious diseases of the respiratory, digestive and urinary tracts, infectious diseases of the throat, nose and ears, and systemic infections, in particular malaria.

Suitable sulfonamides include 2-sulfanylamido-pyridine, 2-sulfanyl amido-thiazole, 2-sulfanylamino-pyrimidy, 2-sulfanamido-4-methyl-pyrimidy, 2-sul Panilamido-4,6-dimethyl-pyrimidi, 4-sulfanamido-2,6-dimethyl-pyrimidy, 5-sulfanylamido-3,4-dimethyl-isoxazole, 3-sulfanylami Fig. 6-Methoxy-pyridazine, 3-sulfanylamido-6-chloro-pyridazine, 4-sulfanylamido-2,6-dimethoxy-pyrimidy, 3-sulfanylamido-2- Phenyl-pyrazole, 2-sulfanylamido-5-methyl-pyrimidy, 2-sulfanylamido-5-methoxy-pyrimidy, 2-sulfanylamido-5-methyl-isoxazole, 2 -Sulfanylamido-4,5-dimethyloxazole, 2-sulfanamido-3-methoxy-pyrazine, 4-sulfanylamido-5,6-methoxy-pyrimidy, 4-sulfanylami Fig. 3-methoxy-1,2,5-thiadiazole and 4-aminobenzene-sulfonyl-guanidines.

Compounds of formula (I) and salts thereof may be bonded in various mixing ratios of the aforementioned sulfone amides, ie, the ratio of the former to the latter is 1: 10-5: 1. In general, the mixing ratio is 1: 1-1: 5. Suitable dosages range from 20-550 mg of the active ingredient of formula (I).

The compound of general formula (I) according to the present invention can be prepared by the conventional method mentioned in Volume 11/2 of the organic chemical method of Hou benweyl (Methcden der organischen). In this method, the imido-acid ester of general formula (II) is reacted with an amine of general formula (III) to obtain amidine of general formula (I), which is converted into an addition salt with pharmaceutically acceptable acid, if necessary. Sometimes.

Wherein R ⁸ is lower alkyl or benzyl having 1-4 carbon atoms;

Imido acid esters of general formula (II) and their preparation are described in German Patent Application No. 27 30 468.3, dated 7.6.

Examples of the amines of general formula (III) include ammonia, methylamine, dimethylamine, diethylamine, benzylamine, 3,4,5-trimethoxy benzylamine, N-phenyl-piperazine, furfurylamine, cyclohexyl Amines, pyrrolidine, piperidine, rocolin and aperine and sulfonamides, ie 2-sulfanamido-pyrimidi, 2-sulfanamido-4-methyl-pyrimidi, 2-sulfanamimi Fig--5-Methyl-pyrimididi, 2-sulfanylamido-5-isopurophyll-pyrimidi, 2-sulfanylamido-5-methoxy-pyrimidy, 3-sulfanylamido-6-meth Oxy-pyridazine, 2-sullanamido-3-methoxy-pyrazine, 3-sulfanylamido-5-methyl-isoxazole and 2-sulfanamido-pyridine.

These compounds can be prepared in the presence or absence of a solvent. Examples of suitable solvents include pyridine, ethanol and mixtures thereof. The reaction temperature is 0-150 ° C, usually 20-150 ° C or temperatures up to the boiling point of the solvent used can be used.

When N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetamido acid ethyl ester and aniline are used as starting materials, the reaction process is as follows. Can be represented.

In order to investigate the action of the compounds according to the present invention, the above compounds were used in animal experiments using the Aronson sepsis model. It was infected with streptococcus free and compared with the conventional drug Trimethoprim. Thirty female rats were infected with lethal streptococcus free and treated 2 hours later with a mixture of 300 mg 2-sulfanamido-4,5-dimethyloxazole with 60 mg of the compound according to the invention. After 44 hours the number of surviving animals was counted and divided by the number of surviving mice from the herd treated with reference material. The numerical value (triproprim factor) obtained therefrom is the degree of application of the compound according to the present invention compared to trimetoprim. F = 2 means that the compounds of the present invention have twice the effect of trimetaprim. The following table shows that the compound according to the present invention is 5.4 times better than trimetapurim.

TABLE 1

General formula

The present invention also relates to the use of the compounds of formula (I) as sulfonamide reinforcing agents and chemotherapeutic agents which contain compounds of formula (II) in combination with sulfonamides in particular as active ingredients and which have been added to conventional carriers and excipients. It is about.

The above-mentioned chemotherapeutic agents are prepared by known methods, for example, using known carriers or excipients and known pharmaceutical preparations, depending on the desired route of administration.

Typical formulations are those suitable for oral administration. Examples thereof include tablets, film tablets, dragees, capsules, pills, powders, solutions and suspensions.

Example 1

16.2 g of N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetamido acid ethyl ester was dissolved in 120 ml of pyridine and dissolved in ethanol. After adding 14 ml of saturated solution, the mixture was stirred at 10 ° C. for 12 hours.

After concentration under reduced pressure, the residue was recrystallized from dioxane to give N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetami having a melting point of 207 캜. 8.6 g (57.7% of theory) were obtained.

Example 2

Stir with one hand 1.8 g of N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acet amido acid ethyl ester, 0.93 g of aniline and 20 ml of anhydrous ethanol After refluxing for 15 hours, the mixture was cooled and 80 ml of water was added, to form N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N at a melting point of 189 ° C. 1.1 g of '-phenyl-acetamidine (53% of theory) were obtained.

Example 3

1.8 g of N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetimido acid ethyl ester was mixed with 20 ml of aqueous 40% dimethylamine solution in 50- After stirring for 10 hours at 60%, the crystalline precipitate was filtered off, washed with water and recrystallized with dioxane to give N- [4-amino-5- (3,4,5-trimethoxybenzyl)-at a melting point of 220 ° C. 1.24 g (69% of theory) of pyrimidi-20-yl] -N ', N'-dimethyl-estamidine were obtained.

Example 4

N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N ', N'- at a melting point of 154 ° C. using the method mentioned in Example 3. Dimethyl- acetamidine was obtained from N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acet amido acid ethylester and diethylamine.

Example 5

N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetamido acid ethyl ester is suspended in 10 ml of N-phenylpiperazine and this mixture is all dissolved. Heated at 65 ° C. until stirred at 90-100 ° C. for 3 hours. After cooling, the mixture was treated with 100 ml of diethyl ether, and the white crystalline precipitate was filtered off and recrystallized with butyl acetate to give N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyridine having a melting point of 197 ° C. Midi-2-yl] -N ', N'-(3-aza-3-phenyl-pentamethylene) -acetamidine 1.6 g (67% of theory) was obtained.

Example 6

Melting point from N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acet imido acid ethyl ester and pyrrolidine using the method according to Example 5 N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N, N-tetramethylene-amitamidine at 198 ° C. was obtained.

Example 7

5.4 g of N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetimido acid ethyl ester and 1.6 g of benzylamine were dissolved in 40 ml of pyridine and 90 DEG C. Stirred for 2 h. After the mixture was concentrated under reduced pressure, the residue was dissolved in 200 ml of warm ethyl acetate and the solution was purified with activated carbon and then cooled. 3.2 g of N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N'-benzyl-acemidine at a melting point of 164 DEG C from this solution 51%) was obtained.

The following compound was prepared by the method according to Example 7.

8. From N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetamido acid ester and 3,4,5-trimethoxy-benzylamine N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N '-(3,4,5-trimethoxybenzyl)-at a melting point of 143 ° C Acetamidine.

9. N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetamido acid ethyl ester and morphine having a melting point of 205 ° C. from N- [4- Amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N ', N'-(3-oxy-pentamethylene) -acet amidine.

10. N- [4 at melting point 184 ° from N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetamido acid ethyl ester and putfurylamine -Amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N'-furfuryl-acet amidine.

11.N- [4-amino-5 from N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetimido acid ethylester and cyclohexylamine -(3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N'-cyclohexyl-acet amidine.

12. N at melting point 248 ° C. from N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetimido acid ethylester and 1-adamantyl amine -[4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N'-adamantyl-acetamididine.

Example 13

N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetimido acid ethyl ester 10.8 g and 2-sulfanyl amido-5-methoxy- 4.2 g of pyrimidy (sulfamethoxydiazine) was dissolved in 80 ml of pyridine, stirred for 12 hours at reflux and concentrated under reduced pressure. The residue was dissolved in warm acetone and treated with activated carbon to give N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N 'at a melting point of 218 ° C. 5.43 g (60.8% of theory) of -4- (5-methoxypyridimi-2-yl) -sulfonamido] -phenyl-acet amidine were determined.

The following compound was prepared by the method according to Example 13.

14.N- [4-Amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetimidoethylester and 2-sulfanamido-5-methyl-pyrimidy N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N'-4- (5-methyl-pyri) of melting point 192 DEG C from (sulferin) Midi-2-yl) -sulfonamido] -phenylacetamidine.

15. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetamido acid ethylester and 2-sulfanamido-pyrimidy (sulfadiazine) N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N '-[4- (pyrimidi-2-) Nil) -sulfonamido] -phenyl-acetamidine.

16. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetamido acid ethyl ester and 2-sulfanyl amido-4-methyl-pyri N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N '-[4- (4- at melting point 162 ° C. from midi (sulfamerazine) Methylpyrimidin-2-yl) -sulfonamido] -phenylacet amidine.

17. N from N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetimido acid ethylester and 4-aminobenzene sulfonylguanidine (sulfaguanidine) -[4-Amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N '-(4-sulfonylguanidino) -phenyl-acetamidine.

18. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetamido acid ethylethyl ether and 3-sulfanamido-5-methyl N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N '-[4- at a melting point of 155 DEG C from isoxazole (sulfamethoxazole) (5-Methyl-isoxazol-3-yl) -sulfone amido] -phenyl-acetamidine.

19. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetamido acid ethyl ester and 3-sulfanamido-6-methoxy- N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N '-[4- at a melting point of 168 ° C from pyridazine (sulfamethoxypyridazine) (6-methoxy-pyridazin-3-yl) -sulfonamido] -phenylacetamidine.

20. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetamido acid ethyl ester and 2-sulfanamido-pyridine (sulpapyridinine N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N '-[4-pyridin-2-yl) -sulfone at a melting point of 37 ° C. from Amido] -phenyl acetamidine.

21.N- [4-Amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetamido acid ethyl ester and 2-sulfanamido-4-isopurophyll N- [4-amino-5- (3,4,5-irimethoxybenzyl) -pyrimidin-2-yl] -N '-[4-5-isopurophyll- at a melting point of 201 ° C. from pyrimidine; Pyrimidin-2-yl) -sulfonamido] -phenyl acetamidine.

22. N- [4-Amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -acetamido acid ethyl ester and 2-sulfanamido-3-methoxypyrazine N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N'- at a melting point of 148 ° C (decomposition) from (sulfamethoxypyrazine, sulfalene) [4- (3-methoxy-pyrazin-2-yl) -sulfonamido] -phenyl acet amidine.

23. 2-Sulfanilamido-4,5-dimethyloxazole 400 mg

N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N'-benzylacetamidine 80 mg

Example 7

The active ingredient was mixed with corn starch and assembled using gelatin aqueous solution. The dried granules were sieved and then the additives were added and mixed. This mixture was formulated into tablets according to known methods.

24. 2-Sulfanilamido-5-methoxy-pyrimidy 160 mg

N- [4-ami-em-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl]-N'-phenyl-acetamidine 80 mg

Example 2

The active ingredient was granulated using an aqueous solution of gelatin and the dried granules were mixed by adding corn starch, talc and magnesium stearate. This mixture was formulated into tablets according to known methods.

27.Sulfanilamido-5-methoxy-pyrimidy 4.00 g

N- [4-dkalsh-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N ', N-dimethyl- acetamidine 2.00 g

Example 3

The finely pulverized active ingredient was suspended in tylose mucus and, on the other hand, all other ingredients were added continuously while stirring to finally make the mixture up to 100.0 g with water.

The active ingredient was granulated using an aqueous solution of gelatin, and then dried granules were mixed with corn starch, talc and magnesium stearate.

This mixture was formulated into tablets by known methods.

25.N- [4-Amino-5- (3,4,5-trimethoxybenzyl)-(pyrimidi) -2-N '-[4-pyrimidin-2-yl) -sulfonamido]- Phenyl-acetamido (Example 15)

The active ingredient was mixed with corn starch and assembled using an aqueous solution of gelatin. The dry granules were sieved and the additives were added and mixed. This mixture was prepared by a known method.

26. N- [4-Amino-5- (3,4,5-trimethoxybenzyl)-(pyrimidine) -2-yl] -N '-[4- (5-methoxy pyrimidine-2- IL) -sulfonamido] -phenylacetamidine 250 mg

Example 13

The active ingredient was granulated using an aqueous solution of gelatin, and the dried fruit was mixed by adding corn starch, talc and magnesium stearate. This mixture was formulated into tablets by known methods.

27.2-sulfanamido-5-methoxy-pyrimidine 4.00 g

N- [4-amino-5- (3,4,5-trimethoxybenzyl) -pyrimidin-2-yl] -N ', N'-dimethyl-misetamidine 2.00 g

Example 3

The finely pulverized active ingredient was suspended in tylose mucus, and on the other hand, all other ingredients were added continuously while stirring, finally making the mixture up to 100.0 g with water.

28. N- [4-Amino-5- (3,4,5-trimethoxy benzyl) -pyrimidin-2-yl] -N ', N'-[4- (5-methyl-pyrimidine-2 -Yl) -sulfonamido] -phenyl-acetamidine 0.300 g

Example 14

The finely pulverized active ingredient was suspended in tylose mucus and, on the other hand, all the other ingredients were added continuously while stirring, finally making the mixture up to 100.0 g with water.

Claims (1)

A process for preparing amidino-benzyl pyrimidy as described in general formula (I), wherein a compound such as the following general formula (III) is reacted with an amine such as general formula (II) in the presence or absence of a solvent.

Wherein R ¹ , R ² and R ³ are the same or different and are hydrogen, methyl, methoxy, or chlorine, R ⁴ is alkyl having 1-6 carbon atoms, or benzyl, and R ⁵ and R ⁶ are the same as each other or As different, hydrogen, lower alkyl having 1-4 carbon atoms, substituted or unsubstituted benzyl, phenyl, cyclohexyl, adamantyl or furfuryl or one of R ⁵ and R ⁶ is -C ₆ H | ₄ -SO ₂ -NH-R ⁷ groups (R ⁷ is

Or a heterocyclic ring having 5-6 elements, the same or different heteroatoms of 1-3, i.e. nitrogen or oxygen, and which may be substituted by chlorine, methyl or methoxy groups), or R ⁵ and R ⁶ represents a saturated heterocyclic ring containing 5-7 elements, all with a nitrogen atom attached to 2 and containing oxygen or> NY group (Y is methyl, benzyl, or phenyl), and R ⁸ is 1-C. Lower alkyl or benzyl four.